| Summary: | Toads in the family Bufonidae contain bufadienolides in their venom, which are characterized by their chemical diversity and high pharmacological potential. American trypanosomiasis is a neglected disease that affects an estimated 8 million people in tropical and subtropical countries. In this research, we investigated the chemical composition and antitrypanosomal activity of toad venom from <i>Rhinella alata</i> collected in Panama. Structural determination using mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy led to the identification of 10 bufadienolides. Compounds identified include the following: 16β-hydroxy-desacetyl-bufotalin-3-adipoyl-arginine ester (<b>1</b>), bufotalin (<b>2</b>), 16β-hydroxy-desacetyl-bufotalin-3-pimeloyl-arginine ester (<b>3</b>), bufotalin-3-pimeloyl-arginine ester (<b>4</b>), 16β-hydroxy-desacetyl-bufotalin-3-suberoyl-arginine ester (<b>5</b>), bufotalin-3-suberoyl-arginine ester (<b>6</b>), cinobufagin-3-adipoyl-arginine ester (<b>7</b>), cinobufagin-3-pimeloyl-arginine ester (<b>8</b>), cinobufagin-3-suberoyl-arginine ester (<b>9</b>), and cinobufagin (<b>10</b>). Among these, three new natural products, <b>1</b>, <b>3</b>, and <b>5</b>, are described, and compounds <b>1</b>–<b>10</b> are reported for the first time in <i>R. alata</i>. The antitrypanosomal activity assessed in this study revealed that the presence of an arginyl-diacid attached to C-3, and a hydroxyl group at C-14 in the structure of bufadienolides that is important for their biological activity. Bufadienolides showed cytotoxic activity against epithelial kidney Vero cells; however, bufagins (<b>2</b> and <b>10</b>) displayed low mammalian cytotoxicity. Compounds <b>2</b> and <b>10</b> showed activity against the cancer cell lines MCF-7, NCI-H460, and SF-268.
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